1) Field of the Invention
The present invention is concerned with novel compounds I which inhibit the angiotensinogen-cleaving action of the natural proteolytic enzyme, renin, with pharmaceutical compositions containing the novel peptides of the present invention as active ingredients, with methods of treating, preventing or managing renin-associated hypertension, hyperaldosteronism, congestive heart failure and glaucoma with diagnostic methods which utilize the novel compounds I of the present invention, as well as processes therefor.
Renin is an endopeptidase (molecular weight about 40,000) produced and secreted by the juxtaglomerular cells of the kidney, which cleaves the naturally-occurring plasma glycoprotein, antiotensinogen, specifically at the 10, 11 peptide bond, i.e., between Leu 10 and Leu 11 in the equine substrate, as described by Skeggs et al, J. Exper. Med. 1957, 106, 439, or between the Leu 10 and Val 11 in the human renin substrate, as elucidated by Tewksbury et al., Circulation 59, 60, Supp. II: 132, October 1979. Renin cleaves angiotensinogen, its protein substrate, to split off the hemodynamically-inactive decapeptide, angiotensin I, which is converted in the lungs, kidney or other tissue by angiotensin-converting enzyme to the potent pressor octapeptide, angiotensin II. Angiotensin II is then believed to cause constriction of the arterioles and to stimulate release of the sodium-retaining hormone, aldosterone, from the adrenal gland and thereby cause a rise in extracellular fluid volume. Thus, the renin-angiotensin system plays an important role in normal cardiovascular homeostasis and in some forms of elevated blood pressure (hypertension).
Inhibitors of angiotensin I converting enzyme have proven useful in the modulation of the renin-angiotensin system. Consequently, specific inhibitors of the limiting enzymatic step that ultimately regulates angiotensin II production, the action of renin on its substrate, have also been sought as effective investigative tools, as well as therapeutic agents in the treatment of hypertension, congestive heart failure, and glaucoma.
Several cyclic renin inhibitor designs have been reported in the literature. In general, the aim of the studies reported was to use the conformational constraints imposed by the cyclic structures to help define the conformation of substrates and inhibitors as they bind to renin. None of these publications set forth possible advantages for inhibitors of this type or claim or establish any advantage for these cyclic inhibitors over their acyclic counterparts.
Early cyclic inhibitor designs used 18-membered or 20-membered rings to enclose a Pro-Phe beta-turn postulated to occur in bound substrate, and yielded inhibitors with moderate potency, comparable to that of acyclic analogs (C. L. Nakaie, M. C. F. Oliveira, L. Juliano, J. L. Pesquero and A. C. M. Paiva in Peptides, Structure and Function. Proceedings of the Eighth American Peptide Symposium, V. J. Hruby, and D. H. Rich, Eds., Pierce Chemical Co., Rockford, Ill., 1983, p. 595; C. R. Nakaie, J. L. Pesquero, M. C. F. Oliveira, L. Juliano and A. C. M. Paiva, in Peptides, Structure and Function. Proceedings of the Ninth American Peptide Symposium, C. M. Dever, V. J. Hruby and K. D. Kopple, Eds., Pierce Chemical Co., Rockford, Ill., 1985, p. 755).
Pairs of cysteine side-chains (P.sub.2 -P.sub.2 ' and P.sub.4 -P.sub.2 ' pairs) have been linked in high molecular weight cyclic inhibitor structures which are based on the P.sub.1 -P.sub.1 ' Phe-Phe sequence, statine, or a reduced peptide isostere. Only the cyclic inhibitors with a Phe-Phe sequence replacing the scissile bond of substrate show potency comparable to acyclic analogs (T. K. Sawyer, D. T. Pals, C. W. Smith, H. S. Saneii, D. E. Epps, D. J. Duchamp, J. B. Hester, R. E. TenBrink, D. J. Staples, A. E. deVaux, J. A. Affholter, G. F. Skala, W. M. Kati, J. A. Lawson, M. R. Schuette, B. V. Kamdar and D. E. Emmert in Peptides, Structure and Function. Proceedings of the Ninth American Peptide Symposium, C. M. Deber, V. J. Hruby and K. D. Kopple, Eds., Pierce Chemical Co., Rockford, Ill., 1985, p. 729).
Two cyclic inhibitor designs investigated by Boger et al., incorporated disulfides constructed from P.sub.2 toward the carboxy terminus, and these had potency comparable to that of an acyclic analog. An amino-terminal cyclic disulfide inhibitor made by connecting P.sub.5 and P.sub.2 homocysteine sidechains encloses a Pro-Phe beta-turn. The optimal ring size for a P.sub.5 -P.sub.2 cycle is found in the 16-membered ring inhibitor, and three other disulfide cycles with cysteine at either P.sub.5 or P.sub.2 (or both), were substantially less potent (J. Boger in Aspartic Proteinases and Their Inhibitors, V. Kostka, Ed., Walter de Gruyter, Berlin, 1985, p. 401; J. Boger in Proceedings of the Third SCI-RSC Medicinal Chemistry Symposium; Special Publication No. 55 of the Royal Society of Chemistry, R. W. Lambert, Ed., Burlington House, London W1V OBN, 1986, p. 271). Please see also U.S. Pat. Nos. 4,477,440 and 4,477,441.
A series of renin inhibitors in which the P.sub.1 side-chain of a "reduced peptide" inhibitor is cyclized onto the alpha-nitrogen atom of alanine at P.sub.2 has been reported (H. Sham, G. Bolis, H. H. Stein, S. W. Fesik, P. A. Marcotte, J. J. Plattner, C. A. Rempel and J. Greer, J. Med. Chem., 31, 284 (1988), but these have only moderate potency.
Although in some of the cases cited above, the ring-size of the cyclic element of the renin inhibitors cited above is similar to those of the cyclic renin inhibitors disclosed herein, the inhibitors of the present case are structurally distinct, and unlike other cyclic renin inhibitors have low molecular weight, show high in vitro potency against human renin, and are orally active.